(a) Field of the Invention
This invention relates to 3-amino-5-(substituted-phenyl)-2-(1H)-pyridinones, their preparation and use as cardiotonics, and to 1,2-dihnydro-5-(substituted-phenyl)-2-oxo-nicotinonitriles, which are useful as cardiotonics and as intermediates in the preparation of said 3-amino-5-(substituted-phenyl)-2(1H)-pyridinones.
(b) Description of the Prior Art
Julia et al., Bull. soc. chim. (France), 2387-2394 (1966), show inter alia the reaction of 1-hydroxymethylene-1-phenyl-2-propanone with .alpha.-cyanoacetamide to produce 2-hydroxy-5-(unsubstituted-phenyl)-6-methylnicotinonitrile and the reaction of 3-dimethylamino-2-phenyl-2-propenal (same as .beta.-dimethylamino-.alpha.-phenylacrolein) with .alpha.-cyanoacetamide to produce 2-hydroxy-5-(unsubtituted-phenyl)nicotinonitrile. These 2-hydroxy compounds, tautomers of the corresponding 1,2-dihydro-2(1H)-pyridinones, were converted to their corresponding carboxylic acids and ethyl or methyl esters and also to their respective 2-chloro compounds and 5-(unsubstituted-phenyl)-3-piperidinecarboxamide derivatives, representative members of which were found to have pharmacological activity resembling that of lysergamide.
Shen et al. [U.S. Pat. No. 3,718,743, issued Feb. 27, 1973] show "5-phenyl-2-piperidinones and 5-phenyl-2-thiopiperidinones in compositions and methods for treating pain, fever and inflammation". The generic teaching of these piperidinones shows that "phenyl" can have one or two substituents at positions 2, 3, 4, 5 and/or 6, e.g., inter alia, nitro, amino, lower-alkyl, lower-alkylamino and lower-alkylmercapto. Various meams of preparing the 5-phenyl-2-piperidinone final products are shown. In one procedure, a 2-chloro-5-phenylpyridine was heated with aqueous sodium hydroxide in dimethylformamide to produce the corresponding 5-phenyl-2(1H)-pyridinones which were then hydrogenated to produce the desired 5-phenyl-2-piperidinones. Among the intermediate 5-phenyl-2(1H)-pyridinones specifically shown is 5-(4-hydroxyphenyl)-2(1H)-pyridinone as well as its preparation by heating the corresponding 5-(4-methoxyphenyl)-2(1H)-pyridinone with pyridine hydrochloride under nitrogen.
Shen et al. [U.S. Pat. No. 3,655,679, issued Apr. 11, 1972, and U.S. Pat. No. 3,703,582, issued Nov. 21, 1972] show as antiinflammatory, analgesic and antipyretic agents various aryl-hydroxy-pyridinecarboxylic acids and lower-alkyl esters thereof, among which are 5-(substituted-phenyl)-2-hydroxynicotinic acids; these latter compounds were prepared by reacting a 2-(substituted-phenyl)-3-dimethylamino-2-propenal with cyanoacetamide to first produce 5-(substituted-phenyl)-2-hydroxynicotinonitrile, illustrated inter alia by the compounds where substituted-phenyl is 4-chlorophenyl, 3,4-dihydroxyphenyl, 4-nitrophenyl, 4-benzoylaminophenyl or 2,6-dimethoxyphenyl. Also shown is the preparation of the corresponding 2-hydroxy-6-methyl-5-(substituted-phenyl)nicotinonitrile by reacting 2-(substituted-phenyl)-acetoacetaldehyde with cyanoacetamide followed by hydrolysis of the nicotinonitrile to the corresponding nicotinic acid; illustrations of intermediate nicotinonitriles produced by this procedure include inter alia the compounds where substituted-phenyl is 2-hydroxyphenyl, 4-methoxyphenyl or 4-aminophenyl.
Lesher and Opalka [U.S. Pat. No. 4,004,012, issued Jan. 18, 1977, and U.S. Pat. No. 4,072,746, issued Feb. 7, 1978] show as cardiotonic agents 3-amino(or cyano)-5-(pyridinyl)-2(1H)-pyridinones and as intermediates, the corresponding 3-carbamyl compounds, alternatively named 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinamide, which are converted to the corresponding 3-amino compounds by reaction with a reagent capable of converting carbamyl to amino, e.g., by heating with an alkali metal hypohalite. A preferred embodiment of these compounds is 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, now generically known as amrinone and alternatively named 5-amino-[3,4'-bipyridin]-6(1H)-one. One method shown for preparing the 3-cyano-5-(pyridinyl)-2(1H)-pyridinones, alternatively named 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinonitriles, is the reaction of .alpha.-(pyridinyl)-.beta.-(dialkylamino)acrolein with .alpha.-cyanoacetamide. U.S. Pat. No. 4,072,746 also shows 3-Q-5-(pyridinyl)-2(1H)-pyridinones where Q is hydrogen, halo, lower-alkylamino, di-(lower-alkyl)amino or NHAc where Ac is lower-alkanoyl or lower-carbalkoxy. The disclosure of U.S. Pat. No. 4,072,746 also is shown in Lesher and Opalka U.S. Pat. Nos. 4,107,315, 4,137,233, 4,199,586 and 4,225,715.
Lesher and Philion [U.S. Pat. No. 4,313,951, issued Feb. 2, 1982] show as cardiotonic agents 3-amino(or cyano or carbamyl)-6-(lower-alkyl)5-(pyridinyl)-b 2(1H)-pyridinones.
Lesher and Singh [U.S. Pat. No. 4,297,362, issued Oct. 27, 1981] show as a cardiotonic agent 4-(3,4-diaminophenyl)pyridine or its salts.
Collins et al. [U.S. Pat. No. 4,302,462, issued Nov. 24, 1981] show as cardiotonic agents 4-[4(or 3)-pyridinyl]-1,2-benzenediol and corresponding dimethyl ether.